It has been estimated that each year, nearly two hundred and fifty thousand men in the United States are diagnosed with prostate cancer and that approximately forty thousand men will die from it; Boring et al., CA Cancer Journal for Clinicians, Volume 44, Number 1, pages 7-26 (1994). Current treatments, which include surgery, radiation and hormone ablation, have some effect on slowing tumor growth but show no significant effect on long term remission or cure; Scher, Current Opinion in Oncology, Volume 3, pages 568-574 (1991). When confined within the organ capsule, prostate carcinoma is relatively easy to treat successfully. However, metastatic disease, which targets to the axial skeleton about eighty percent of the time, is nearly always refractory to treatment; Franks, Journal of Pathology and Bacteriology, Volume 72, pages 603-611 (1956); and Huben et al., CA Cancer Journal for Clinicians., Volume 36, Number 5, pages 274-292 (1986).
The dissemination of prostate carcinoma cells to the bones of the central spine has been ascribed to the presence of paravertebral vessels; Zetter et al., Prostate Cancer and Bone Metastasis, edited by Karr and Yamanaka, Plenum Press, New York (1992), at pages 39-43. However, this direct metastatic route does not explain why the level of tumor cell proliferation in bone is often higher than in the prostate gland itself; Jacobs, Urology, Volume 21, Number 4, pages 337-344 (1983). Additionally, bone metastases are often the first evidence of progression to androgen-independent prostate carcinoma; Logothetis et al., Seminars in Oncology, Volume 21, Number 5, pages 620-629 (1994). The uncoupling of prostate carcinoma cell growth from hormone responsiveness signals the failure or irrelevance of hormone ablation therapy and the increasing ability of prostate carcinoma cells to proliferate in response to paracrine and autocrine peptide growth factors; Thompson, Cancer Cells, Volume 2, Number 11, pages 345-354 (1990); and Scher et al., Seminars in Urology, Volume 10, Number 1, pages 55-64 (1992). Although clinical relevance has not been convincingly established, several growth factors, including bFGF, aFGF, EGF, TGFa, and PDGF, have been isolated from the conditioned media of human prostate carcinoma cells in vitro, and from prostate tissue in vivo.
Bone stromal cells also produce factors that stimulate the proliferation of prostate carcinoma cells; Chackal-Roy et al., Journal of Clinical Investigation, Volume 84, pages 43-50 (1989). The interactions of prostate stromal and epithelial cells with regard to KGF and bFGF have been well established; Chung, Cancer Biology, Volume 4, pages 183-192 (1993). However, the interactions between bone stromal cells and metastatic prostate carcinoma cells has not yet been studied as closely. Conditioned media from bone stromal cells, but not skeletal muscle, keratinocytes or kidney epithelial cells, stimulates the A-414 proliferation of prostate carcinoma cells; see Zetter et al. above. Furthermore, bone stromal cell media is not active on kidney carcinoma or melanoma cells, suggesting tissue specific interactions between bone stromal cells and prostate carcinoma cells. This tissue specificity has been confirmed in vivo by co-inoculating stromal cells and LNCaP prostate carcinoma cells, which are normally non-tumorigenic, into nude mice; Gleave et al., Cancer Research, Volume 51, pages 3753-3761 (1991). In these studies, bone or prostate stromal cells supported tumor growth in viva, whereas lung or kidney stromal cells did not.
One factor, identified in bone stromal cell cultures, that stimulates prostate cell proliferation is transferrin, which is a well-characterized protein involved in the transport of iron across cell membranes; Rossi et al., Proceedings of the National Academy of Science USA, Volume 89, pages 6197-6201 (1992). In addition, published PCT patent application PCT/US95/09261 (WO 96/04379) describes the isolation and expression of DNA encoding a bone and prostate-derived growth factor, termed BPGF-1. The BPGF-1 gene was found to be expressed predominantly in bone, prostate tissue and seminal vesicles, and BPGF-1 polypeptide stimulated the proliferation of prostatic epithelial cells in vitro.